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46670402.der.pdf
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46670402
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Zeta-Cypermethrin
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52315-07-8
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129064
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Nemec, M. (2005) A Dietary Developmental Neurotoxicity Study of Zeta-Cypermethrin Technical in Rats: Final Report. Project Number: A2004/5809, WIL/105018. Unpublished study prepared by WIL Research Laboratories, Inc. 2260 p.
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2005.0
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Zeta-Cypermethrin: In a developmental neurotoxicity study (MRID 46670402), Zeta-cypermethrin technical (81.8% a.i.; lot # PL03-0427) was administered in the diet to 25 mated female Crl:CD®(SD)IGS BR rats/group at nominal concentrations of 0, 50, 125, or 300 ppm from gestation day (GD) 6 through lactation day (LD) 21. Average doses to the animals, adjusted for purity, were 0, 2.9, 7.4, or 17.3 mg/kg/day, respectively, during gestation and 0, 7.1, 17.5, or 39.8 mg/kg/day, respectively, during lactation. Functional Observations (FO) were performed on 25 dams/group on GDs 10 and 15 and on all surviving dams that delivered offspring on LDs 10 and 21. On postnatal day (PND) 4, litters were culled to eight offspring, with at least three males and three females per litter. Offspring were allocated for detailed clinical observations (FO) and assessment of motor activity, auditory startle response, and learning and memory, as well as for neuropathology at study termination (PND 72). On PND 21, the whole brain was collected from 10 pups/sex/dose group, weighed, and subjected to micropathologic examination and morphometric analysis. Pup physical development was evaluated by body weight. The age of sexual maturation (vaginal opening in females and preputial separation in males) was assessed.
One control female was found dead late in gestation; necropsy revealed a ruptured uterus and late resorptions. All remaining animals survived to scheduled sacrifice. No treatment-related clinical signs of toxicity were observed during the daily examinations.
Absolute body weight of dams was similar between the treated and control groups throughout gestation. However, body weight gain by the high-dose group was slightly less (n.s.) than that of controls for each interval, resulting in overall gestational weight gain (GD 0-20) by the high-dose animals that was 90% of the control group level. Food consumption by the high-dose group was significantly less (p ¿ 0.05 or 0.01) than that of the control group during GDs 6-9 (87% of controls) and GDs 6-20 (96% of controls). Throughout lactation, mean body weight of the high-dose group was significantly less (p ¿ 0.05 or 0.01; 92-95% of control value) than that of controls. Food consumption by the high-dose group was significantly less than that of the control group (p ¿ 0.05 or 0.01; 87-92% of controls) throughout lactation. The observed changes in body weight, body weight gain and food consumption were not considered to be adverse, due to the small magnitude of the change. No treatment-related effects were observed in reproductive parameters, and gross necropsy was unremarkable.
No treatment-related effect on the mean number of pups born, mean live litter size, percentage of males per litter, pup survival, or clinical signs was observed. Pup body weights were similar between the treated and control groups on PNDs 1-11. On PNDs 13-21, mean body weight was significantly decreased in the high-dose female offspring (90-92% of control value) and was slightly (n.s.) decreased in the high-dose male offspring (93-94% of control value). Mean body weight gain was significantly decreased in the high-dose females (86-89% of control value) for all intervals during PNDs 7-17 and for PND 4-21 (87% of controls). Mean weight gain was significantly decreased in the high-dose males (86% of control value) during the PND 11-13 interval. Post-weaning body weight and body weight gain were similar between the treated and control groups. The average age and body weight at attainment of sexual maturation was not affected by treatment.
No treatment-related FO changes were observed in males or females on testing days PNDs 4, 11, 45 and 60 or in females on PND 22. On PND 22, high-dose males had significantly reduced fore-limb grip strength (146.8 vs 174.8 for controls; p ¿ 0.05), and four animals were observed with drooping palpebral closure compared with none of the controls.
No significant difference in total motor activity was found between the treated and control groups on any testing day. However, a trend towards increased activity in high-dose males and decreased activity in high-dose females was observed on some testing days. On PND 17, high-dose males had a slight increase in total motor activity (124% of controls), resulting from increased subsession motor activity, particularly during final two 15 minute intervals (150% of controls; n.s. and 281% of controls; p ¿ 0.05). This increased activity in the final subsessions indicates that less habituation occurred in the high dose PND 17 males, compared to controls. In females, decreased motor activity was seen at the high dose on both PNDs 17 and 21 (71% and 70% of controls, respectively; n.s.). On PND 17, this decrease, due to less activity during the first two 15 minute subsessions (47-62% of controls; p ¿ 0.01), was considered to be equivocal in nature. The decreases in activity on PND 21 (45-86% of controls; n.s.) were not considered biologically significant because they were seen only in the subsession data (not in total or ambulatory counts), only in one sex (females), only on postnatal day 21 (not in measurements taken at three other time periods), and the differences did not reach statistical significance.
Auditory startle response, learning and memory, and gross and qualitative microscopic findings were not affected by treatment.
A slight, non-dose related increase in male brain weights was noted at the high dose on PND 21 (104% of controls, n.s.). A statistically significant increase in the vertical thickness of the cortex was observed in high dose PND 21 females (106% of controls; p ¿ 0.05). This sole brain morphometric change was determined to occur in isolation, only in female pups on day 21, and was not considered biologically significant because when the values of individual treated animals were compared with individual control animals, the incidence and magnitude of the change suggested a low concern. No statistically or biologically significant changes were seen in any other brain areas in male or female pups at any time period.
The maternal NOAEL is 300 ppm (17.3 mg/kg/day), the highest dose tested; a LOAEL was not established.
The offspring LOAEL is 300 ppm (17.3 mg/kg/day to dams), based on decreased body weights and body weight gains of females. The offspring NOAEL is 125 ppm (7.4 mg/kg/day to dams).
This study is classified Acceptable/Non-Guideline and may be used for regulatory purposes, however it does not satisfy the guideline requirement for a developmental neurotoxicity study in rats ((OPPTS 870.6300, §83-6); OECD 426 (draft)) pending the evaluation of available positive control data.
[This classification scheme is applicable only to Developmental Neurotoxicity (DNT) studies. The DNT Work Group determined that this study can be classified as Acceptable. This study does not satisfy the guideline requirements for a developmental neurotoxicity study and is classified as NonGuideline pending review of all available positive control data. J. Rowland, 03/13/2008]
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Developmental-Neurotoxicity
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NA [870.6300, Developmental neurotoxicity study]
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Oral
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No Duration Period; GD 6 through LD 21
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53857.0
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2008-03-13
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2008-12-30
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Added by
Madison Feshuk
on Apr 25, 2022
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